The general objective of this proposal is to develop a center of the study of the relationship between aberrant carbohydrate metabolism and developmental events in animals, established disease patterns in humans, its effect on the offspring and the mechanisms leading to the diabetic state in both animals and humans. It is anticipated that this effort will provide a more rational therapy for diabetic patients. The specific objectives are to a) clarify the relationship between diabetes in women and the occurrence of congenital abnormalities in their offspring, b) determine the mechanisms operative in regulation of carbohydrate metabolism during immediate extrauterine adaptation, c) study the factors modulating insulin receptor number and/or affinity during development, d) study the mechanisms leading to hyperinsulinemia and its effects on hepatic hormone clearance, hepatic ketogenesis and glycogenolysis in the genetically obese rodent, e) develop an external programmable microelectronic control system for insulin administration in the control of diabetes mellitus in humans after appropriate observations in diabetic dogs, with an implantable pump reservoir system exploring the feasibility of intraperitoneal versus intravenous insulin therapy, and f) clarify the interrelationships between insulin binding, internalization and degradation and the factors that regulate the metabolic disposition of insulin.